Applications of Neural Stem Cells in Spinal Cord Injury

神经干细胞在脊髓损伤中的应用

• 批准号: 8534981
• 负责人: Itzhak Fischer
• 金额: $ 26.21万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8534981
• 关键词: Acute; Address; Adult; Alkaline Phosphatase; Area; Axon; Behavioral; Brain Injuries; Brain Stem; Cell Nucleus; Chondroitinases; Chronic; Cicatrix; Deafferentation procedure; Degenerative Disorder; Development; Electric Stimulation; Electrophysiology (science); Embryo; Environment; Evoked Potentials; Exercise; Experimental Designs; FOS gene; GRP gene; Gene Expression; Growth; Hyaluronidase; Individual; Injury; Instruction; Lentivirus Vector; Lesion; Mediating; Modeling; Natural regeneration; Neurodegenerative Disorders; Neurons; Physiological; Principal Investigator; Property; Proteins; Protocols documentation; Quality of life; Rattus; Recovery; Role; Sensory; Site; Societies; Spinal cord injury; Staging; Synapses; System; Testing; Time; Training; Transgenic Organisms; Translating; Transplantation; Viral Vector; adeno-associated viral vector; axon growth; axon regeneration; central nervous system injury; density; design; dorsal column; functional improvement; functional restoration; improved; improved functioning; in vivo; nerve stem cell; neuronal replacement; neurotrophic factor; novel; postsynaptic; progenitor; programs; repaired; research study; restoration; sensory system; stem cell biology; synaptogenesis; tool; vector

Despite progress in elucidating neural stem cell properties and using them for transplantation, the challenges of neuronal cell replacement following CNS injury remain difficult to resolve. This proposal will use transplants of neuronal and glial restricted progenitors (NRP/GRP) to reconnect the disrupted sensory system after acute and chronic spinal cord injury (SCI). The experiments are designed to build neuronal relays across a dorsal column lesion reconnecting the denervated dorsal column nucleus (DCN). The proposal addresses important issues related to application of stem cell biology to CNS injury, including how to generate graft derived neurons, direct their axon growth, overcome the inhibitory environment of the injury, and, most importantiy, how to form functional synapses with the denervated target. We will continue our studies that demonstrated the principles of relay formation with NRP/GRP transplants by testing specific hypotheses for improving the functional aspects of the relay and advance this strategy to chronic SCI. In Aim 1, we will test the role of synaptic density and activity-induced plasticity in producing stable and functional synaptic connections at the DCN target. We propose that a) synaptic activity with target neurons will improve through summation of the evoked potentials at the target site by increasing synaptic density (more axons) and reducing inhibition of perineuronal nets at the DCN, and b) synapse stability will improve with time, with task-specific activity, and with stimulation of the sensory relay. In Aim 2 we will test the hypothesis that denervated targets can be reconnected and retrained to correctly interpret sensory information at a chronic injury stage. Specifically, we will test a) how to promote host sensory axons to grow into the site of a chronic injury, and b) how to promote connectivity at the target, where the DCN has been subject to prolonged deafferentation. To achieve connectivity in the chronic injury, we will use neurotrophins, chondroitinase (delivered by novel viral vectors), and exercise/training protocols. This relay model allows us to go beyond the current focus on regeneration, exploit the advantages of embryonic neurons produced by neural stem cells, and examine the steps needed to restore connectivity and improve function in a well-defined system. RELEVANCE (See instructions): Spinal cord injury has devastating effects on quality of life accompanied by a heavy financial burden to individuals and society. This proposal addresses potential therapies for spinal cord injury using transplants of neural stem cells to restore connectivity and function. The strategies developed in this project are also relevant to brain injury and other neuro-degenerative disorders that require neuronal cell replacement

尽管在阐明神经干细胞特性并将其用于移植方面取得了进展，但仍面临挑战 中枢神经系统损伤后神经元细胞替代的问题仍然难以解决。本提案将使用 移植神经元和神经胶质限制性祖细胞（NRP/GRP）以重新连接受损的感觉 急性和慢性脊髓损伤（SCI）后的系统。这些实验旨在构建神经元 穿过背柱病变重新连接去神经的背柱核（DCN）。这 该提案解决了与干细胞生物学应用于中枢神经系统损伤相关的重要问题，包括如何 生成移植源性神经元，指导其轴突生长，克服损伤的抑制环境， 最重要的是，如何与去神经靶标形成功能性突触。我们将继续我们的 通过测试特定的研究，证明了 NRP/GRP 移植的中继形成原理 改善中继功能方面的假设并将这一策略推进慢性 SCI。瞄准 1，我们将测试突触密度和活动诱导的可塑性在产生稳定和功能性方面的作用 DCN 目标处的突触连接。我们建议 a) 与目标神经元的突触活动将会改善 通过增加突触密度（更多轴突）对目标部位的诱发电位进行求和 并减少 DCN 神经周围网络的抑制，并且 b) 突触稳定性将随着时间的推移而改善， 特定任务的活动，并刺激感觉传递。在目标 2 中，我们将检验以下假设： 去神经化的目标可以重新连接并重新训练，以正确解释长期的感觉信息 损伤阶段。具体来说，我们将测试a）如何促进宿主感觉轴突生长到慢性病的部位 损伤，以及 b) 如何促进 DCN 长期遭受损伤的目标处的连接 传入神经阻滞。为了实现慢性损伤的连接，我们将使用神经营养素、软骨素酶 （由新型病毒载体传递）和运动/训练方案。这种中继模型使我们能够超越 当前关注再生，利用神经干产生胚胎神经元的优势 细胞，并检查在明确定义的系统中恢复连接和改善功能所需的步骤。 相关性（参见说明）： 脊髓损伤对生活质量产生毁灭性影响，并给人们带来沉重的经济负担 个人和社会。该提案提出了使用移植物治疗脊髓损伤的潜在疗法 神经干细胞恢复连接和功能。该项目中制定的策略也 与脑损伤和其他需要神经元细胞替代的神经退行性疾病相关